Disorders of the central nervous system (CNS) are highly prevalent and can affect the brain and/or the spinal cord, resulting in neurological or psychiatric disorders, and occasionally a severe impairment of quality of life. The development of new methods of treatment has addressed a multitude of disorders; but, however, still lags behind other therapeutic areas. This is due to several factors including the complexity of the diseases and the problem of delivering drugs through the blood-brain barrier (BBB). The development of new therapies for CNS disorders could provide patients with significant improvements in quality of life, and reduce the economic burden on health-care systems.
CNS disorders involving inflammation and/or neurodegeneration account for a large proportion of disorders affecting the CNS. They include widely known diseases such as Alzheimer's Disease, Parkinson's Disease and Multiple Sclerosis.
Multiple sclerosis (MS) is a disease of the central nervous system (CNS). It is estimated that number of people affected by MS amounts to 2-2.5 million (approximately 30 per 100,000) worldwide. Pathological manifestations of MS can include multiple inflammatory foci, plaques of demyelination, neuronal injury or loss within the brain or spinal cord, and neuronal dysfunction. MS is typically accompanied by neurological symptoms of variable degrees, including motor, sensory and cognitive deficits, ataxia and visual impairment.
Although the events triggering the onset of MS are still not fully understood, most evidence points toward an autoimmune etiology, possibly together with environmental factors or genetic predisposition. Many elements of the cascade of events leading to MS have been studied in experimental autoimmune encephalomyelitis (EAE), an animal model of autoimmune inflammatory diseases of the CNS which resembles MS in many respects (Constantinescu et al., 2011). Active EAE is induced by immunization of susceptible animals with CNS tissue or myelin peptides, for example myelin basic protein (MBP), proteolipid protein (PLP) or myelin oligodendrocyte glycoprotein (MOG), or their encephalitogenic fragments such as PLP139-151 or MOG35-55, and appropriate adjuvants. Passive or adoptive-transfer EAE can be induced by transferring pathogenic, myelin-specific T cells to recipient animals. In 2006, Krishnamoorthy et al. further developed transgenic mouse with MOG specific T and B cell receptors that spontaneously develops an inflammatory demyelinating disease resembling Devic's disease, which is often considered a variant of MS.
α-melanocyte-stimulating hormone (α-MSH) is a 13 amino acid peptide derived from a large precursor hormone called pro-opiomelanocortin (POMC). Post-translational cleavage of POMC gives rise to α-MSH in a tissue-specific manner. It has been detected in various regions of the brain and peripheral organs including the skin. Cells producing α-MSH include keratinocytes, melanocytes, Langerhans cells, monocytes, macrophages, endothelial cells, fibroblasts and mast cells. It has been established that α-MSH is not only involved in melanogenesis, but also plays a role in immunity and inflammation (see Luger et al. (2003) for review).
α-MSH exerts its effects through activation of cell-surface bound melanocortin receptors. Five melanocortin receptors (MC-1R to MC-5R) are known. They belong to the G-protein coupled receptors with seven transmembrane domains and are expressed in a cell- and tissue specific manner (see Brzoska et al. for review). The majority of anti-inflammatory effects of α-MSH are associated with to the detection of MC-1R, however, several in vivo studies have linked α-MSH activity to MC-4R (Carniglia et al. 2013).
The anti-inflammatory potential of α-MSH and its role in immunological cascades has been elucidated by several studies. It has been shown to down-regulate the production of pro-inflammatory cytokines (IL-1, IL-6, TNF-α, IL-2, IFN-γ, IL-4, IL-13) and the expression of co-stimulatory molecules (CD86, CD40) and adhesion molecules (ICAM-1, VCAM-1, E-selectin) on antigen-presenting cells. Furthermore, the production of the cytokine synthesis inhibitor IL-10 is up-regulated by α-MSH (Brzoska et al. (2008), Luger et al. (2003)).
The large majority of studies concerned with the investigation of the neuroprotective effect of melanocortins assess the effects of α-MSH, as reviewed in Catania (2008), but fail to recognized the therapeutic potential of NDP-MSH in MS treatment. Brod and Hood (2008) reported that orally administered α-MSH delayed disease onset and decreased disease severity in EAE. Mice were fed with 1, 10 or 100 μg α-MSH starting one week prior to EAE induction by active immunization and continuing through day 14 post immunization. α-MSH prevented or delayed disease onset and was able to reduce the clinical score of affected animals (patented in U.S. Pat. No. 7,807,143). However, the fact that preventive administration of relatively high dosages was necessary on a daily basis renders the approach impracticable for treatment of MS in humans.
Two groups pursued a gene therapy approach in order to deliver sufficient amounts of α-MSH: Yin et al. (2003) generated expression constructs encoding peptides with α-MSH activity and assessed their potential for treatment of EAE in mice. Intramuscular injection of 100 μg of DNA constructs was accomplished concurrently with EAE induction and repeated weekly for a total period of 4 weeks. Treatment with the DNA constructs resulted in delayed disease onset (about 2 days) and a decreased mortality, accounting for the slight reduction of the mean clinical score that was observed.
Han et al. (2008) employed activated transduced T cells specific for the CNS proteolipid (PLP) 139-151 as α-MSH “shuttles”. α-MSH producing T cells exhibited an altered cytokine secretion profile and, when transferred to animals with induced or established EAE, could reduce disease incidence delay disease onset. However, although the idea of using auto-reactive T cells as targeted α-MSH shuttles may seem intriguing, the fact that 12.5% of healthy recipient animals developed EAE renders this approach untenable with regard to safety and acceptance as a potential MS therapy.
Therapeutic treatment using α-MSH is hampered because of its inherent instability and short plasma half-life, and its weak receptor interaction (Rudman et al., 1983; Sawyer et al., 1980), resulting in the need of repeated high-dose administration.
However, in 1980 Sawyer et al. succeeded in synthesizing the synthetic α-MSH analog NDP-MSH which exhibited superior biological properties including prolonged biological activity, enhanced potency and resistance to enzymatic degradation (EP0292291). Today, NDP-MSH is marketed as SCENESSE® as a photoprotective drug and has been authorized by the European Medicine's Agency for treatment of erythropoietic protoporphyria. The role of NDP-MSH in inflammatory processes has been assessed, i.e., by Carniglia et al. (2013) who reported that NDP-MSH stimulates the release of IL-10 and TGF-β via MC-4R signaling in rat primary astrocytes and microglia in vitro. The mere observation that rat primary cells—obtained from healthy rat pups—release anti-inflammatory cytokines upon addition of NDP-MSH in vitro can however not suffice to foresee the surprising effects of NDP-MSH on the complex events contributing to disease onset and progression in adult MS model animals. Further, the observations presented herein clearly indicate involvement of MC-1R signaling whereas the effects observed by Carniglia et al. were linked to the detection of MC-4R expression, thereby indicating that the present inventors have revealed a novel mechanism of action of NDP-MSH in inflammatory and/or neurodegenerative processes within the CNS. Ter Laak et al. (2003) discovered that the α-MSH analog melanotan-II is effective in nerve regeneration and neuroprotection, but did not investigate the effect of NDP-MSH, let alone in MS treatment.
There is currently no cure for MS. Therapeutic treatment of MS includes disease-modifying and symptomatic treatments. FDA-approved disease-modifying agents for treatment of relapsing-remitting MS include immunosuppressive agents (mitoxantrone and teriflunomide), immunomodulatory agents such as glatiramer acetate (GA) and the cytokine inhibitor IFN-β, cell-migration modifying therapies including natalizumab and finglomod and neuroprotective agents such as dimethyl-fumarate. While treatment of relapsing-remitting MS is still hampered by adverse side effects or limited clinical efficacy, therapeutic options for secondary progressive MS or primary progressive MS are severely limited (for review see Chen et al. (2012)). There still exists a need in the art to develop alternative drugs for multiple sclerosis treatment.
The technical problem can thus be seen in the provision of an alternative treatment for inflammatory and/or neurodegenerative disorders of the CNS or multiple sclerosis.